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A new gene editing study is poised on the cusp of medical history because it holds out the prospect of providing a cure for hemophilia

Hemophilia is a rare incurable life-threatening blood disorder

People with hemophilia have little or no protein needed for normal blood clotting

Severe forms of the disorder may result in spontaneous and excessive bleeding

In recent history many people with hemophilia died before they reached adulthood because of the dearth of effective treatments

A breakthrough therapy in the 1980s was contaminated with deadly viruses

A cure for hemophilia?

A study led by researchers from Barts Health NHS Trust and Queen Mary University London and published in a 2017 edition of the New England Journalof Medicinehas made a significant step forward towards finding a cure for hemophilia A, a rare incurable life threatening-blood disorder, which is caused by the failure to produce certain proteins required for blood clotting. In recent history only a few people with hemophilia survived into adulthood. This was because of the dearth of effective treatments and any small cut or internal hemorrhaging after even a minor bruise was often fatal.

Theroyal disease

There are 2 main types of hemophilia: A and B. Both are rare congenital bleeding disorders sometimes referred to as “the royal disease,” because in the 19th and 20th centuries hemophilia affected European royal families. Queen Victoria of England is believed to have been a carrier of hemophilia B, a rarer condition than hemophilia A. 2 of Victoria’s 5 daughters (Alice and Beatrice) were also carriers. Through marriage they passed on the mutation to various royal houses across Europe including those of Germany, Russia and Spain. Victoria’s son Prince Leopold was diagnosed with hemophilia A when he was a child. He died at 31 and throughout his life had a constant staff of doctors around him.

Epidemiology

The worldwide incidence of hemophilia A is about 1 in 5,000 males, with approximately 33% of affected individuals not having a family history of the disorder, which in their cases result from a new mutation or an acquired immunologic process. Only 25% of people with hemophilia receive adequate treatment; most of these are in developed nations. In 2016 there were some 7,700 people diagnosed with the condition in the UK, 2,000 of whom had a severe form with virtually no blood clotting protein. In the US there are some 20,000 people living with the disorder. Morbidity and death from hemophilia are primarily the result of haemorrhage, although HIV and hepatitis infections became prominent in patients who received therapies with contaminated blood products prior to the mid-1980s: see below.

Etiology

Hemophilia A and B are similar disorders. Both are caused by an inherited or acquired genetic mutation, which reduces or eliminates the coagulation genes referred to as factor VIII for hemophilia A, and factor IX for hemophilia B. Factors VIII and IX are essential blood clotting proteins, which work with platelets to stop or control bleeding. The amount of the protein present in your blood and its activity determines the severity of symptoms, which range from mild to severe. Factors VIII and IX deficiencies are the best-known and most common types of hemophilia, but other clotting factor deficiencies also exist. Factors VIII and IX are encoded in genes and located on the X chromosomes, which come in pairs. Females have 2 X chromosomes, while males have 1 X and 1 Y chromosome. Only the X chromosome carries the genes related to clotting factors. A male who has a hemophilia gene on his X chromosome will have hemophilia. Since females have 2 X chromosomes, a mutation must be present in both copies of the gene to cause the hemophilia. When a female has a hemophilia gene on only 1 of her X chromosomes, she is a "carrier” of the disorder and can pass the gene to her children. Sometimes carriers have low levels of a clotting factor and therefore have symptoms of hemophilia, including bleeding.

Hemophilia A and B

Hemophilia A and B affect all races and ethnic groups equally. Hemophilia B is the second most common type of hemophilia and is less common than factor VIII deficiency. Notwithstanding, the result is the same for people with hemophilia A and B: they both bleed more easily and for a longer time than usual. The differences between hemophilia A and B are in the factor that is either missing or at a low level. The treatments to replace factors A and B are different. Hemophilia A needs to be treated with factor VIII, and hemophilia B with factor IX. Giving factor VIII to someone with hemophilia B will not help to stop the bleeding.

People with mild hemophilia have few symptoms on a day-to-day basis, but may bleed excessively for example during surgery, whilst those with a severe form of the disorder may have spontaneous bleeds. Severe hemophilia tends to be diagnosed in childhood or as part of screening in families known to have bleeding disorders. People who do not have hemophilia have a factor VIII activity of 100%, whereas people who have severe hemophilia A have a factor VIII activity of less than 1%. In severe forms, even the slightest injury can result in excessive bleeding as well as spontaneous internal bleeding, which can be life threatening. Also, the pressure of massive bleeding into joints and muscles make hemophilia one of the most painful diseases known to medicine. Without adequate treatment, many people with hemophilia die before they reach adulthood. However, with effective replacement therapy, life expectancy is about 10 years less than that of males without hemophilia, and children can look forward to a normal life expectancy. Replacement therapy entails concentrates of clotting factor VIII (for haemophilia A) or clotting factor IX (for haemophilia B) being slowly dripped or injected into a vein to help replace the clotting factors that are missing or low.

Brief history of treatments

In the 1950s and 60s fresh frozen plasma (FFP) was the principal therapy for hemophilia A and B. However, because each bag of FFP contained only very small amounts of the clotting agents, large amounts of plasma had to be transfused to stop bleeding episodes and people with the conditions had to be hospitalized. In some countries FFP is still the only product available for treating hemophilia.

In the mid-1960s Judith Pool, an American scientist, made a significant advance in haemophilia therapy when she discovered that the sludge, which sank to the bottom of thawing plasma was rich in factor VIII (but not IX) and could be frozen and stored as “cryoprecipitate plasma”. This more concentrated clotting factor VIII became the preferred treatment for severe hemophilia A as it required smaller volumes and patients could receive treatment as outpatients. Notwithstanding cryoprecipitate is less safe from viral contamination than concentrates and is harder to store and administer.

The tainted blood scandal

In the early 1970s drug companies found they could take the clotting factors VIII and IX out of blood plasma and freeze-dry them into a powder. This quickly became the treatment of choice as it could be used to treat hemophilia at home. There was a huge demand for the new freeze-dried product, and drug companies distilled the plasma of large groups of donors, sometimes as many as 25,000, to meet the demand. This led companies seeking substantial supplies of blood to pay prisoners and others to give blood. Some donors were addicted to drugs and infected with the HIV virus and hepatitis C. By the early 1980s, human blood, plasma and plasma-derived products used in therapies for hemophilia were discovered to be transmitting potentially deadly blood-borne viruses, including hepatitis viruses and HIV. So the same advanced substance being used to treat people with hemophilia was also responsible for causing sufferers prolonged illnesses and premature death.

Infected hemophilia treatments in the UK

A report published in 2015 by a UK All Party Parliamentary Group on Haemophilia found that 7,500 people in Britain with the disorder were infected with the contaminated blood products. According to Tainted Blood, a group set up in 2006 to campaign on behalf of people with hemophilia, 4,800 people were infected with hepatitis C, a virus that causes liver damage and can be fatal. Of these, 1,200 were also infected with HIV, which can cause AIDS, and some 2,400 sufferers died prematurely.

A 2017 UK official enquiry

In 1991 the UK government made ex-gratia payments to hemophilia patients infected with HIV, averaging £60,000 each, on condition that they dropped further legal claims. The extent of infection with hepatitis C was not discovered until years later. Campaigners unearthed evidence suggesting that UK officials in the Department of Health knew or suspected that the imported factor concentrates were risky as early as 1983. Notwithstanding, NHS England is said to havecontinued to administer the contaminated concentrates to patients with hemophilia. In 2017 the UK government set up an inquiry into the NHS contaminated blood scandal.

A new scientific era

In the early 1980s, soon after HIV was identified, another significant breakthrough occurred in the treatment of hemophilia when manufacturers used genetically engineered cells that carry a human factor gene (called recombinant products). Today, all commercially prepared factor concentrates are treated to remove or inactivate blood-borne viruses. Also, scientists have a better understanding of the etiology of the disease and are able to detect and measure its inhibitors and know how to eliminate them by manipulating the immune system.

A cure for haemophilia A

Researchers, led by John Pasi, Director of the Haemophilia Centre at Barts Health NHS Trust and Professor of Haemostasis and Thrombosis at Queen Mary University London, have successfully carried out the first gene editing study for hemophilia A. The study enrolled 13 patients across England and injected them with a copy of their missing gene, which allows their cells to produce the essential blood-clotting agent factor VIII. Researchers followed participants for up to 19 months, and findings showed that 85% had normal or near normal levels of the previously missing factor VIII clotting agent and all participants were able to stop their previously regular haemophilia A treatment: they were effectively cured.

Gene editing

Gene editing is particularly relevant for diseases such as hemophilia A where, until the recent UK study reported in this Commentary, there was no cure. Gene editing allows doctors to prevent and treat a disorder by inserting a healthy gene into a patient’s cells to replace a mutated or missing gene that causes the disease. The technique has risks and is still under consideration to ensure that it is safe and effective. In 2015, a group of Chinese scientists edited the genomes of human embryos in an attempt to modify the gene responsible for β-thalassemia, another potentially fatal blood disorder.

Expanding the study

According to Pasi, "We have seen mind-blowing results, which have far exceeded our expectations. When we started out we thought it would be a huge achievement to show a 5% improvement, so to actually be seeing normal or near normal factor levels with dramatic reduction in bleeding is quite simply amazing. We really now have the potential to transform care for people with haemophilia using a single treatment for people who at the moment must inject themselves as often as every other day." Pasi and his colleagues are expected to undertake further studies with participants from the USA, Europe, Africa and South America.

Takeaway

Hemophilia is a life-changing, often painful and debilitating disorder. In recent history there was a dearth of effective therapies and people with the disorder barely survived into adulthood. More recent scientific advances that used concentrated blood products to improve treatment were contaminated with deadly viruses, which further destroyed the lives of sufferers, and in many cases led to their premature death. The study, undertaken by Pasi and his colleagues, is on the cusp of medical history because it has the potential to provide a cure for what has been an incurable life-changing disease. Notwithstanding, it is worth bearing in mind that scientific discovery is rarely quick and rarely proceeds in a straight line.